Instructions Ariprazole tablets 10 mg blister No. 60
Composition
active ingredient: aripiprazole;
1 tablet contains 10 mg of aripiprazole (calculated as 100% dry aripiprazole);
Excipients: hydroxypropylmethylcellulose; croscarmellose sodium; lactose, monohydrate; microcrystalline cellulose; citric acid, monohydrate; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: 10 mg tablets: white or almost white tablets, round in shape, with a flat surface, with a score.
Pharmacotherapeutic group
Psycholeptics. Antipsychotics. Other neuroleptics.
ATX code N05A X12.
Pharmacological properties
Pharmacodynamics
Mechanism of action.
The therapeutic effect of aripiprazole in the treatment of schizophrenia and bipolar I disorder is due to a combination of partial agonism at dopamine D2 and serotonin 5-HT1a receptors, and antagonism at serotonin 5-HT2a receptors. Aripiprazole has been shown to exhibit antagonistic properties in animal models of dopaminergic hyperactivity and agonistic properties in animal models of dopaminergic hypoactivity. Aripiprazole has high binding affinity in vitro for dopamine D2 and D3 receptors, serotonin 5-HT1a and 5-HT2a receptors, and moderate affinity for dopamine D4, serotonin 5-HT2c and 5-HT7, alpha-1 adrenergic receptors, and histamine H1 receptors. Aripiprazole also has moderate affinity for serotonin receptors and no appreciable affinity for muscarinic receptors. Interactions with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.
Pharmacokinetics
Absorption.
Aripiprazole is well absorbed, with peak plasma concentrations occurring 3-5 hours after administration. Aripiprazole undergoes minimal first-pass metabolism. Absolute oral bioavailability is 87%. High-fat meals do not affect the pharmacokinetics of aripiprazole.
Distribution.
Aripiprazole is widely distributed in body tissues. The volume of distribution is 4.9 l/kg, indicating extensive extravascular distribution. When administered in therapeutic doses, aripiprazole and dehydroaripiprazole are more than 99% bound to serum proteins, primarily albumin.
Biotransformation.
Aripiprazole is extensively metabolized in the liver, primarily by dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies have shown that CYP3A4 and CYP2D6 are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the major systemic drug. At steady state, dehydroaripiprazole, its active metabolite, accounts for approximately 40% of the plasma AUC of aripiprazole.
Breeding.
The mean elimination half-life of aripiprazole is approximately 75 hours in CYP2D6 extensive metabolizers and approximately 146 hours in CYP2D6 poor metabolizers.
The total clearance of aripiprazole is 0.7 mL/min/kg, and is primarily due to hepatic clearance. Following a single oral dose of 14C-labeled aripiprazole, approximately 27% was excreted in the urine and approximately 60% in the feces. Less than 1% of unchanged aripiprazole was excreted in the urine, and approximately 18% of unchanged aripiprazole was excreted in the feces.
Pharmacokinetics in special patient groups.
Children.
The pharmacokinetics of aripiprazole and dehydroaripiprazole in patients aged 10 to 17 years were similar to those in adults after adjusting for differences in body weight.
Elderly patients.
There are no differences between the pharmacokinetics of aripiprazole in healthy elderly volunteers and younger patients.
Sex.
There are no differences between the pharmacokinetics of aripiprazole in healthy men and women.
Smoking and race.
Population pharmacokinetic evaluation revealed no clinically significant race-related differences or effects of smoking on the pharmacokinetics of aripiprazole.
Kidney dysfunction.
The pharmacokinetic characteristics of aripiprazole and dehydroaripiprazole were found to be similar in both patients with severe renal disease and young healthy volunteers.
Liver dysfunction.
There are insufficient data on the metabolic characteristics of aripiprazole in patients with hepatic impairment.
Indication
Ariprazole is indicated for the treatment of schizophrenia in adults.
Aripiprazole is also indicated for the treatment of moderate to severe manic episodes in bipolar I disorder, and for the prevention of new manic episodes in adults who have previously experienced manic episodes and who have responded to aripiprazole treatment.
Contraindication
Hypersensitivity to aripiprazole or to any other component of the drug.
Interaction with other medicinal products and other types of interactions
Given the primary effects of aripiprazole on the central nervous system, caution should be exercised when prescribing aripiprazole with other drugs that affect the CNS due to possible cross-adverse reactions, such as sedation.
It is also necessary to refrain from drinking alcohol during therapy with aripiprazole. Aripiprazole should be used with caution in combination with other drugs that prolong the QT interval or disrupt electrolyte balance.
Potential effects of other drugs on the action of aripiprazole.
The inhibitor of hydrochloric acid secretion, H2-histamine receptor antagonist famotidine reduces the rate of absorption of aripiprazole, but this effect is not considered clinically significant.
Aripiprazole is metabolized by multiple pathways involving CYP2D6 and CYP3A4, but not CYP1A. Therefore, no dose adjustment is necessary for smokers.
Quinidine and other CYP2D6 inhibitors.
The dose of aripiprazole should be reduced by approximately half when co-administered with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have a similar effect, so the dose reduction should be similar when used with them.
Ketoconazole and other CYP3A4 inhibitors.
In CYP2D6 poor metabolizers, concomitant administration of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole than in CYP2D6 extensive metabolizers. If concomitant use of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefits should outweigh the potential risks to the patient. The dose of aripiprazole should be reduced by approximately half when aripiprazole and ketoconazole are used concomitantly. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, could theoretically have similar effects and should therefore be reduced accordingly.
After discontinuation of the CYP2D6 or CYP3A4 inhibitor, the aripiprazole dose should be increased to the level used prior to initiation of concomitant therapy.
A small increase in aripiprazole concentrations is possible with concomitant use of weak inhibitors of CYP3A4 (e.g. diltiazem or escitalopram) or CYP2D6.
Carbamazepine and other CYP3A4 inhibitors.
The dose of aripiprazole should be doubled when co-administered with carbamazepine. Other strong CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John's wort) are expected to have similar effects and an appropriate dose increase is therefore necessary. After discontinuation of strong CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended dose.
Valproate and lithium.
No clinically significant changes in aripiprazole concentrations were observed when valproate or lithium were co-administered with aripiprazole.
Serotonin syndrome.
Cases of serotonin syndrome have been reported in patients taking aripiprazole; particularly when used concomitantly with other serotonergic drugs such as SSRIs (selective serotonin reuptake inhibitors/selective serotonin/norepinephrine reuptake inhibitors) or with drugs that increase aripiprazole concentrations.
Potential effects of aripiprazole on the effects of other drugs.
Aripiprazole is unlikely to cause clinically important drug interactions mediated by the enzymes CYP2D6 (dextromethorphan/3-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan).
No clinically significant changes in valproate, lithium or lamotrigine concentrations were observed when aripiprazole was co-administered with valproate, lithium or lamotrigine.
Application features
When treated with neuroleptics, improvement in the patient's clinical condition may take from several days to several weeks. During this period, patients should be carefully monitored.
Suicidality: The emergence of suicidal behaviour is common in patients with psychotic illnesses and affective disorders and has in some cases been observed shortly after the initiation of neuroleptic treatment or the switch from one neuroleptic to another, including treatment with aripiprazole. Treatment with neuroleptics should be accompanied by close monitoring of patients who are at increased risk.
It is known that there is no increased risk of suicidal tendencies with the use of aripiprazole compared to the use of other neuroleptics.
Cardiovascular disorders: Aripiprazole should be used with caution in patients with a history of cardiovascular disease (myocardial infarction or ischemic heart disease, heart failure or conduction disorders), cerebrovascular disorders, conditions that predispose patients to hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or hypertension, including progressive or malignant hypertension.
Cases of venous thromboembolism (VTE) have been observed during treatment with neuroleptics.
QT prolongation: As with other neuroleptics, aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia: If symptoms of tardive dyskinesia develop in a patient taking aripiprazole, dose reduction or discontinuation should be considered. These symptoms may temporarily worsen or even recur after discontinuation of treatment.
Other extrapyramidal symptoms: Akathisia and parkinsonism have been observed in children with aripiprazole. If signs of other extrapyramidal symptoms appear, dose reduction should be considered and the patient should be closely monitored clinically.
Neuroleptic malignant syndrome (NMS): NMS is a complex of symptoms associated with the use of neuroleptic drugs, which can be potentially fatal.
Clinical manifestations of NMS include hyperpyrexia (extremely high body temperature), muscle rigidity, altered mental status, and signs of autonomic nervous system dysfunction (irregular pulse or blood pressure, tachycardia, increased sweating, and cardiac arrhythmia). Additional features may include elevated creatine kinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, isolated cases of elevated creatine kinase and rhabdomyolysis have been reported, not necessarily associated with NMS. If a patient develops symptoms of NMS or an unexplained very high body temperature without additional clinical manifestations of NMS, all neuroleptic medicinal products, including aripiprazole, should be discontinued.
Seizures: Rare cases of seizures have been reported with aripiprazole. Therefore, aripiprazole should be used with caution in patients with a history of epilepsy or conditions associated with seizures.
Elderly patients with psychosis on the background of dementia.
Increased mortality: Aripiprazole has been associated with an increased risk of death in elderly patients with psychosis secondary to Alzheimer's disease. Although the causes of death varied, most deaths were cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Cerebrovascular adverse reactions: Cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack), including fatalities, have been observed in elderly patients with psychosis associated with Alzheimer's disease.
A pronounced relationship between drug doses and the occurrence of cerebrovascular adverse reactions in patients taking aripiprazole was noted.
Aripiprazole is not indicated for the treatment of psychosis in dementia.
Hyperglycemia and diabetes mellitus: Hyperglycemia, in some cases extremely severe and associated with ketoacidosis or hyperosmolar coma, including fatal outcomes, has been reported in patients taking atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and a family history of diabetes. There is no precise comparative assessment of the risks of adverse reactions associated with hyperglycemia in patients taking aripiprazole and other atypical antipsychotics. Patients taking any antipsychotic, including aripiprazole, should be closely monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes mellitus should be monitored regularly for elevated glucose levels.
Hypersensitivity: As with other drugs, hypersensitivity reactions may occur with aripiprazole.
Weight gain: Patients with schizophrenia and bipolar mania often experience weight gain due to comorbid conditions, use of neuroleptics known to cause weight gain, and lack of a healthy lifestyle; this phenomenon can lead to serious complications. Cases of weight gain with aripiprazole have generally been observed in patients with significant risk factors such as diabetes, thyroid disorders, or a history of pituitary adenoma.
Aripiprazole does not cause clinically significant weight gain in adults. In clinical trials in adolescent patients with bipolar mania, aripiprazole was associated with weight gain after 4 weeks of treatment. If weight gain becomes clinically significant, a dose reduction should be considered (see section 4.8).
Pathological gambling and other impulse control disorders: Pathological gambling and the inability to control this impulse have been reported in patients treated with aripiprazole. Hypersexuality, compulsive shopping, binge eating or eating disorders, and other impulsive and compulsive behaviors have also been reported. It is important that patients and their caregivers report the development of new or previously described disorders during treatment with aripiprazole. Symptoms of impulse control disorders may be related to the underlying disorder; however, there have been occasional reports of resolution of the impulse control disorders with dose reduction or discontinuation of treatment. Impulse control disorders may be harmful to the patient and others if they are not recognized. If such disorders develop while taking aripiprazole, consideration should be given to reducing the dose or discontinuing treatment.
Lactose: Ariprazole tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients with comorbid ADHD (attention deficit hyperactivity disorder): Despite the high frequency of comorbidities of bipolar I disorder and ADHD, there are very limited data on the safety of concomitant use of aripiprazole and stimulants, and extreme caution is required when these agents are co-administered.
Falls: Aripiprazole may cause drowsiness, orthostatic hypotension, and motor and sensory instability, which may lead to falls. Caution should be exercised when treating patients at increased risk and treatment should be initiated at lower initial doses (e.g., elderly or debilitated patients).
Ability to influence reaction speed when driving vehicles or other mechanisms
Aripiprazole, like other neuroleptics, may affect the ability to drive due to adverse reactions from the nervous system and visual organs (see section "Adverse reactions"). During treatment, it is recommended to refrain from driving or working with other mechanisms until the individual sensitivity of patients to the drug is known.
Use during pregnancy or breastfeeding
Pregnancy.
There are no adequate and well-controlled studies of aripiprazole in pregnant women. Congenital anomalies have been reported, but a causal relationship to aripiprazole has not been established. Available animal data do not exclude the possibility of embryofetotoxicity. Patients should be advised to inform their physician if they become pregnant or intend to become pregnant while taking aripiprazole. Due to insufficient information on the safety of aripiprazole during pregnancy, it should be used only if the expected benefit to the mother justifies the potential risk to the fetus.
Neonates exposed to neuroleptics (including aripiprazole) during the third trimester of pregnancy may experience adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration. There have been reports of agitation, increased or decreased muscle tone, tremor, drowsiness, respiratory distress, or feeding difficulties. Therefore, close observation of such neonates is necessary.
Breastfeeding.
Aripiprazole/metabolites are excreted in breast milk. If necessary, breastfeeding should be discontinued.
Method of administration and doses
Adults.
Schizophrenia: The recommended starting dose of Ariprazole® is 10 or 15 mg/day, and the maintenance dose is 15 mg/day. This dose is taken once daily without regard to meals.
Ariprazole is effective in the dose range of 10 to 30 mg/day. Increased efficacy has not been demonstrated with doses exceeding 15 mg/day, although individual patients may benefit from higher doses.
The maximum daily dose should not exceed 30 mg.
Manic episodes in bipolar I disorder: The recommended starting dose of Ariprazole is 15 mg. This dose is taken once daily with or without food. The drug can be prescribed as monotherapy or as part of combination therapy. For individual patients, dose escalation may be effective. The maximum daily dose should not exceed 30 mg.
Patients with hepatic impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment. There are insufficient data to make recommendations for patients with severe hepatic impairment. The dose should be adjusted with caution in these patients. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.
Patients with renal impairment: No dose adjustment is required for patients with renal impairment.
Elderly: The efficacy of Ariprazole in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older has not been established. Given the greater sensitivity of this patient population, lower starting doses should be considered when other clinical factors permit.
Gender: No dose adjustment is required based on the patient's gender.
Smoking: Given the metabolic pathway of aripiprazole, no dose adjustment is required for smokers.
Dose adjustment due to interactions: When potent CYP3A4 or CYP2D6 inhibitors are co-administered with aripiprazole, the aripiprazole dose should be reduced. If a CYP3A4 or CYP2D6 inhibitor is removed from the combination regimen, the aripiprazole dose should be increased.
When strong CYP3A4 inducers are co-administered with aripiprazole, the aripiprazole dose should be increased. If the CYP3A4 inducer is removed from the combination regimen, the aripiprazole dose should be reduced to the recommended dose.
Children
Ariprazole in this dosage is not recommended for use in children.
Overdose
In adult patients, cases of intentional or accidental acute overdose with aripiprazole, doses up to 1260 mg, have been described without subsequent fatal outcome. Potentially medically significant symptoms observed included lethargy, increased blood pressure, drowsiness, tachycardia, nausea, vomiting, and diarrhea.
In addition, there have been reports of accidental overdose of aripiprazole alone (up to 195 mg) in children, which was not fatal. Potentially medically significant symptoms observed included drowsiness, transient loss of consciousness, and extrapyramidal symptoms.
Treatment of overdose should include supportive care, airway management, oxygen therapy, mechanical ventilation, and symptom control. The possibility of multiple drug overdose should be considered. Therefore, immediate cardiovascular monitoring should be initiated, including continuous ECG monitoring for arrhythmias.
After a confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring of the patient's condition are necessary until recovery.
Activated charcoal (50 g) administered 1 hour after aripiprazole administration reduced aripiprazole Cmax by approximately 41% and AUC by approximately 51%, indicating the potential efficacy of activated charcoal in the treatment of overdose.
Although information on the effect of hemodialysis on the treatment of aripiprazole overdose is lacking, it is unlikely that hemodialysis would be useful in the treatment of overdose because aripiprazole is extensively bound to plasma proteins.
Adverse reactions
The most common adverse reactions were akathisia and nausea.
The frequency of adverse reactions was determined using the following criteria:
common (≥ 1/100 - < 1/10) and uncommon (≥ 1/1,000 - < 1/100) reactions.
Metabolism and nutrition: common – diabetes mellitus, uncommon – hyperglycemia; endocrine system: uncommon – hyperprolactinemia; mental: common – anxiety, insomnia, restlessness; uncommon – depression, hypersexuality; nervous system: common – extrapyramidal disorders, akathisia, tremor, dizziness, drowsiness, sedation, headache; uncommon – tardive dyskinesia, dystonia; visual system: common – blurred vision; uncommon – diplopia; cardiac: uncommon – tachycardia; vascular system: uncommon – orthostatic hypotension; respiratory system, thoracic and mediastinal organs: uncommon – hiccups; digestive system: common – dyspepsia, vomiting, nausea, constipation, hypersalivation;
general disorders: frequent – fatigue.
Blood and lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia; Immune system disorders: allergic reactions (e.g. anaphylactic reactions, angioedema, tongue swelling, facial swelling, pruritus or urticaria); Endocrine disorders: diabetic ketoacidosis, diabetic hyperosmolar coma; Metabolism and nutrition disorders: weight gain or loss, anorexia, hyponatremia; Psychiatric disorders: agitation, nervousness, pathological gambling, aggression, suicide attempts, suicidal thoughts and suicide, impulse control disorders, overeating, compulsive shopping, poriomania; Nervous system disorders: speech disorders, neuroleptic malignant syndrome (NMS), grand mal convulsive seizure, serotonin syndrome; Visual disorders: oculogyric crisis; Cardiac: QT prolongation, ventricular arrhythmia, sudden death, cardiac arrest, torsades de pointes, bradycardia; Vascular: syncope, hypertension, venous thromboembolism (including pulmonary embolism and deep vein thrombosis); Respiratory, thoracic and mediastinal: oropharyngeal spasm, laryngospasm, aspiration pneumonia; Digestive: pancreatitis, dysphagia, gastrointestinal discomfort, diarrhea; Liver and biliary: hepatic failure, jaundice, hepatitis, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma-glutamyltransferase (GGT), increased alkaline phosphatase; Skin and subcutaneous tissue disorders: rash, photosensitivity reactions, alopecia, increased sweating;
Musculoskeletal and connective tissue disorders: rhabdomyolysis, myalgia, muscle rigidity; pregnancy, postpartum and perinatal conditions: drug withdrawal syndrome in newborns; renal and urinary tract disorders: urinary incontinence, urinary retention; genitals and breast disorders: priapism; general complications and reactions at the injection site: temperature regulation disorders (e.g. hypothermia, hyperthermia), chest pain, peripheral edema; laboratory tests: increased creatine phosphokinase, increased blood glucose, fluctuations in blood glucose, increased glycosylated hemoglobin.
Expiration date
3 years.
Storage conditions
Store out of the reach of children, in the original packaging at a temperature not exceeding 25ºС.
Packaging
10 tablets in a blister. 6 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
"Pharma Start" LLC.
Location of the manufacturer and its business address
Ukraine, 03124, Kyiv, Vaclav Havel Boulevard, 8.
